rs1052555

Variant names:

• chr19-45352266-G-A
• rs1052555
• NM_000400.4:c.2133C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45352266-G-A
• chr19-45352266-G-C
• chr19-45352266-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000400.4(ERCC2):​c.2133C>T​(p.Asp711Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,738 control chromosomes in the GnomAD database, including 80,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6022 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74695 hom.)
• Consequence: ERCC2 NM_000400.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.818
• Publications: 79 publications found

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-45352266-G-A is Benign according to our data. Variant chr19-45352266-G-A is described in ClinVar as Benign. ClinVar VariationId is 256018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.2133C>T	p.Asp711Asp	synonymous	Exon 22 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.2061C>T	p.Asp687Asp	synonymous	Exon 22 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.2055C>T	p.Asp685Asp	synonymous	Exon 21 of 22	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2133C>T	p.Asp711Asp	synonymous	Exon 22 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.2133C>T	p.Asp711Asp	synonymous	Exon 22 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.2061C>T	p.Asp687Asp	synonymous	Exon 21 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38856 AN: 152004 Hom.: 6024 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.282 AC: 70750 AN: 251206 AF XY: 0.295

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.0651

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.312 AC: 455390 AN: 1461616 Hom.: 74695 Cov.: 47 AF XY: 0.314 AC XY: 228392 AN XY: 727104

African (AFR) AF: 0.102 AC: 3406 AN: 33478

American (AMR) AF: 0.159 AC: 7132 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9786 AN: 26132

East Asian (EAS) AF: 0.0433 AC: 1719 AN: 39700

South Asian (SAS) AF: 0.337 AC: 29057 AN: 86252

European-Finnish (FIN) AF: 0.390 AC: 20786 AN: 53356

Middle Eastern (MID) AF: 0.358 AC: 2059 AN: 5756

European-Non Finnish (NFE) AF: 0.327 AC: 363442 AN: 1111844

Other (OTH) AF: 0.298 AC: 18003 AN: 60376

GnomAD4 genome AF: 0.255 AC: 38849 AN: 152122 Hom.: 6022 Cov.: 32 AF XY: 0.257 AC XY: 19127 AN XY: 74360

African (AFR) AF: 0.111 AC: 4626 AN: 41498

American (AMR) AF: 0.207 AC: 3162 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1248 AN: 3468

East Asian (EAS) AF: 0.0607 AC: 315 AN: 5188

South Asian (SAS) AF: 0.328 AC: 1577 AN: 4814

European-Finnish (FIN) AF: 0.396 AC: 4185 AN: 10576

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22711 AN: 67970

Other (OTH) AF: 0.262 AC: 553 AN: 2108

Alfa AF: 0.303 Hom.: 19989

Bravo AF: 0.230

Asia WGS AF: 0.160 AC: 561 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.344

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Xeroderma pigmentosum, group D (2)
-	-	1	Cerebrooculofacioskeletal syndrome 2 (1)
-	-	1	Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.34
DANN	Benign	0.85
PhyloP100		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1052555; hg19: chr19-45855524; COSMIC: COSV67266435; COSMIC: COSV67266435;